Determining the optimal dose in the development of anticancer agents

Area of Science:

• Pharmacology
• Drug Development
• Clinical Trials

Background:

• Optimal drug dosing remains a significant challenge in pharmaceutical development.
• Current strategies, like using the maximum tolerated dose (MTD) for cytotoxic drugs, often overlook critical clinical pharmacology aspects.
• Developing targeted agents requires a shift from toxicity-based to efficacy-based dose optimization, considering disease-specific antitumour effects.

Purpose of the Study:

• To highlight the limitations of current dose-finding strategies in drug development.
• To advocate for a revised approach to dose optimization, emphasizing efficacy and clinical pharmacology.
• To underscore the importance of addressing pharmacokinetic variability and influencing factors in early-phase trials.

Main Methods:

• Review of standard practices in phase I trials for cytotoxic and targeted agents.
• Discussion of pharmacokinetic variability and its impact on dose-effect relationships.
• Emphasis on the need for expanded cohorts and consideration of patient-specific factors.

Main Results:

• The maximum tolerated dose (MTD) approach may not be sufficient for all drug types, particularly targeted agents.
• Interindividual pharmacokinetic variability, influenced by factors like bioavailability, drug interactions, and adherence, complicates dose optimization.
• Efficacy-based dose selection, informed by expanded phase I trials, is crucial for targeted therapies.

Conclusions:

• Drug development must evolve beyond MTD to incorporate clinical pharmacology and individualized patient factors.
• Expanded phase I trials focusing on efficacy and addressing pharmacokinetic variability are essential for optimizing drug doses.
• A comprehensive approach considering patient-specific variables is vital for successful phase II and III studies.